Isothiazolone derivative and microbicidal composition comprising the same as active ingredient

ABSTRACT

There is disclosed a novel isothiazolone derivative of the formula: ##STR1## wherein X 1  and X 2  are the same or different and are independently hydrogen, chlorine or bromine; and R is haloalkoxy. The isothiazolone derivative is effective as a microbicide. Also disclosed are a microbicidal composition containing the isothiazolone derivative as an active ingredient, and an intermediate compound for use in the production of the isothiazolone derivative.

FIELD OF THE INVENTION

present invention relates to a novel isothiazolone derivative and amicrobicidal composition comprising the isothiaolone derivative as anactive ingredient. The present invention also relates to an intermediatecompound for use in the production of the isothiazolone derivative.

BACKGROUND OF THE INVENTION

There are disclosed some isothiazolone derivatives in the U.S. Pat. Nos.3,761,488 and 4,127,687. These isothiazolone derivatives do not havesatisfactory effects of preventing or inhibiting the growth ofmicroorganisms such as bacteria and fungi.

SUMMARY OF THE INVENTION

The present inventors have intensively studied to develop a novelmicrobicide, which can prevent various troubles caused bymicroorganisms. As a result, they have found that particularisothiazolone derivatives have excellent effects of destroying orinhibiting microorganisms, thereby completing the present invention.

Thus, the present invention provides an isothiazolone derivative of theformula: ##STR2## wherein X¹ and X² are the same or different and areindependently hydrogen, chlorine or bromine;. and R is haloalkoxy. Thepresent invention also provides a microbicidal composition comprisingthe isothiazolone derivative (I) as an active ingredient and anintermediate compound for use in the production of the isothiazolonederivative (I).

DETAILED DESCRIPTION OF THE INVENTION

In the isothiazolone derivative (I), the substituent R is haloalkoxy,usually C₁ -C₈ haloalkoxy, and preferably C₁ -C₄ haloalkoxy. Typicalexamples of the haloalkoxy are fluoroalkoxy such as difluoromethoxy,trifluoromethoxy, chlorodifluoromethoxy, pentafluoroethoxy and1,1,2,2-tetrafluoroethoxy.

The isothiazolone derivative (I) of the present invention has excellentmicrobicidal activity against various microorganisms including thefollowing bacteria and fungi.

Bacteria:

Genera of Bacillus, Clostridium, Enterococcus, Flavobacterium,Klebsiella, Micrococcus, Proteus, Pseudomonas, Escherichia,Staphylococcus, Desulphovibrio, Enterobacter, Achrcrnobacter,Cellulomonas, Paracolabactrum, Sphaerotilus, Sporocytophage,Gallionella, Leptothrix, Beggiatoa and Aerobacter.

Fungi:

Genera of Aspergillus, Penicillium, Cladosporium, Aureobasidium,Tyromyces, Coriolus, Myrothecium, Fusarium, Rhizopus, Mucor, Epicoccum,Trichoderma, Phoma, Geotrichum and Monilia.

The isothiazolone derivative of the formula (I) wherein X¹ is hydrogencan be prepared by reacting a disulfide of the formula (II): ##STR3##wherein R is as defined above, with a halogenating agent. Theisothiazolone derivative of the formula (I) wherein X¹ is chlorine orbromine can be prepared by reacting the isothiazolone derivative of theformula (I) wherein X¹ is hydrogen, with a halogenating agent.

The above reaction is usually carded out in the presence or absence of asolvent at a temperature of 0° to 150° C. for a period of 1 to 24 hours.The halogenating agent is used in an amount of 1 to 10 equivalents toone equivalent of the disulfide (II) or the isothiazolone derivative ofthe formula (I) wherein X¹ is hydrogen.

Typical examples of the halogenating agent are chlorine gas, sulfurylchloride, bromine, N-chlorosuccinimide and N-bromosuccinimide.

Examples of the solvent are aliphatic hydrocarbons such as hexane,heptane, ligroin and petroleum ether; aromatic hydrocarbons such asbenzene, toluene and xylene; halogenated hydrocarbons such aschloroform, carbon tetrachloride, dichloroethane, chlorobenzene anddichlorobenzene; ketones such as acetone, methyl ethyl ketone, methylisobutyl ketone, isophorone and cyclohexanone; fatty acids such asformic acid, acetic acid and oleic acid; alcohols such as methanol,ethanol, isopropanol, t-butanol, octanol, cyclohexanol, methylcellosolve, diethylene glycol and glycerin; esters such as ethylformate, ethyl acetate, butyl acetate and diethyl carbonate; nitrocompounds such as nitroethane and nitrobenzene; nitriles such asacetonitrile and isobutyronitrile; tertiary amines such as pyridine,methylamine, N,N-diethyianfline, tributylamine and N-methyl morpholine;acid amides such as formamide, N,N-dimethylformamide and acetamide; andsulfur compounds such as dimethyl sulfoxide and sulfolane. Thesesolvents can be used alone or in combination.

After completion of the reaction, the reaction mixture is subjected toan ordinary post-treatment such as organic solvent extraction andconcentration. When sulfuryl chloride is used as the halogenating agent,a saturated aqueous solution of sodium hydrogen carbonate may be addedto the reaction mixture, if necessary, before the organic solventextraction and concentration. The reaction product may be purified, ifnecessary, by a purification procedure such as chromatography,distillation or recrystallization. Thus, the isothiazolone derivative(I) of the present invention can be obtained.

Typical examples of the isothiazolone derivative (I) which can beprepared in this manner are shown in Table 1; these examples are,however, to be construed as merely illustrative, and not limitations ofthe present invention in any way whatsoever.

                  TABLE 1                                                         ______________________________________                                         ##STR4##                                                                     Compound No.   X.sup.1                                                                             X.sup.2    R                                             ______________________________________                                         (1)           H     H          2-OCF.sub.3                                    (2)           H     H          3-OCF.sub.3                                    (3)           H     H          4-OCF.sub.3                                    (4)           H     H          2-OCF.sub.2 H                                  (5)           H     H          3-OCF.sub.2 H                                  (6)           H     H          4-OCF.sub.2 H                                  (7)           H     H          2-OCF.sub.2 CF.sub.2 H                         (8)           H     H          3-OCF.sub.2 CF.sub.2 H                         (9)           H     H          4-OCF.sub.2 CF.sub.2 H                        (10)           H     H          4-OCF.sub.2 Cl                                (11)           Cl    Cl         2-OCF.sub.3                                   (12)           Cl    Cl         3-OCF.sub.3                                   (13)           Cl    Cl         4-OCF.sub.3                                   (14)           Cl    Cl         2-OCF.sub.2 H                                 (15)           Cl    Cl         3-OCF.sub.2 H                                 (16)           Cl    Cl         4-OCF.sub.2 H                                 (17)           Cl    Cl         2-OCF.sub.2 CF.sub.2 H                        (18)           Cl    Cl         3-OCF.sub.2 CF.sub.2 H                        (19)           Cl    Cl         4-OCF.sub.2 CF.sub.2 H                        (20)           Cl    Cl         4-OCF.sub.2 Cl                                (21)           H     Cl         2-OCF.sub.3                                   (22)           H     Cl         3-OCF.sub.3                                   (23)           H     Cl         4-OCF.sub.3                                   (24)           H     Cl         2-OCF.sub.2 H                                 (25)           H     Cl         3-OCF.sub.2 H                                 (26)           H     Cl         4-OCF.sub.2 H                                 (27)           H     Cl         2-OCF.sub.2 CF.sub.2 H                        (28)           H     Cl         3-OCF.sub.2 CF.sub.2 H                        (29)           H     Cl         4-OCF.sub.2 CF.sub.2 H                        (30)           H     Cl         4-OCF.sub.2 Cl                                (31)           Cl    H          2-OCF.sub.3                                   (32)           Cl    H          3-OCF.sub.3                                   (33)           Cl    H          4-OCF.sub.3                                   (34)           Cl    H          2-OCF.sub.2 H                                 (35)           Cl    H          3-OCF.sub.2 H                                 (36)           Cl    H          4-OCF.sub.2 H                                 (37)           Cl    H          2-OCF.sub.2 CF.sub.2 H                        (38)           Cl    H          3-OCF.sub.2 CF.sub.2 H                        (39)           Cl    H          4-OCF.sub.2 CF.sub.2 H                        (40)           Cl    H          4-OCF.sub.2 Cl                                (41)           Br    Br         2-OCF.sub.3                                   (42)           Br    Br         3-OCF.sub.3                                   (43)           Br    Br         4-OCF.sub.3                                   (44)           Br    Br         2-OCF.sub.2 H                                 (45)           Br    Br         3-OCF.sub.2 H                                 (46)           Br    Br         4-OCF.sub.2 H                                 (47)           Br    Br         2-OCF.sub.2 CF.sub.2 H                        (48)           Br    Br         3-OCF.sub.2 CF.sub.2 H                        (49)           Br    Br         4-OCF.sub.2 CF.sub.2 H                        (50)           Br    Br         4-OCF.sub.2 Cl                                ______________________________________                                    

The disulfide (II) which is an intermediate compound for use in theproduction of the isothiazolone derivative (I) Can be prepared throughthe following pathway: ##STR5## wherein Y is halogen and R is as definedabove.

That is, 3,3'-dithiopropionic acid (III) is halogenated with ahalogenating agent to give an acid halide (IV), which is then reactedwith aniline derivative (V) in the presence of a base to give thedesired disulfide (II).

The respective steps will hereinafter be explained in detail.

Step 1: Halogenation of 3,3'-dithiopropionic acid (Ill) into acid halide(IV)

The reaction is usually carried out in a solvent and, if necessary, inthe presence of a catalyst, at a temperature of 0° to 150° C. for aperiod of 0.5 to 20 hours. Examples of the halogenating agent arethionyl chloride, phosphorus pentachloride, phosphorus trichloride andphosgene. Examples of the catalyst are pyridine, triethylamine andN,N-dimethylformamide. The halogenating agent and catalyst are used inamounts of 2 to 5 equivalents and 0.05 to 0.25 equivalent, respectively,to one equivalent of 3,3'-dithiopropionic acid (III).

Step 2: Reaction of acid halide (IV) with aniline derivative (V) to givedisulfide (II)

The reaction is usually carried out in a solvent and in the presence ofa base at a temperature of 0° to 150° C. for a period of 1 to 24 hours.Examples of the base are inorganic bases such as sodium hydroxide,potassium hydroxide and potassium carbonate; and organic bases such astriethylamine and pyridine. The aniline derivative (V) and the base areused in amounts of 2 to 2.2 equivalents and 2 to 3 equivalents,respectively, to one equivalent of the acid halide (IV).

Typical examples of the solvent which can be used in steps 1 and 2 arealiphatic hydrocarbons such as hexane, heptane, ligroin and petroleumether; aromatic hydrocarbons such as benzene, toluene and xylene;halogenated hydrocarbons such as chloroform, dichloroethane,chlorobenzene and dichlorobenzene; ethers such as diethyl ether,diisopropyl ether, dioxane, tetrahydrofuran and diethylene glycoldimethyl ether; esters such as ethyl formate, ethyl acetate, butylacetate and diethyl carbonate; nitro compounds such as nitroethane andnitrobenzene; nitriles such as acetonitrile and isobutyronitrile; acidamides such as formamide, N,N-dimethylformamide and acetamide; andsulfur compounds such as dimethyl sulfoxide and sulfolane. Thesesolvents can be used alone or in combination. In step 2, water may beadded to the reaction system for double phase reaction.

After completion of the reaction in step 1, the reaction mixture issubjected to an ordinary post-treatment such as removal of the solvent.The acid halide (IV) may be isolated, if necessary, by distilling orpurifying the reaction product. Alternatively, the reaction mixtureobtained in step 1 may be used directly for the reaction in step 2.

After completion of the reaction in step 2, the reaction mixture issubjected to an ordinary post-treatment such as removal of the solvent,extraction with a solvent and concentration, followed by, if necessary,depositing crystals with the addition of aqueous hydrochloric acid andwashing the crystals with water. The disulfide (II) may be isolated, ifnecessary, by purifying the reaction product by chromatography orrecrystallization.

Typical examples of the disulfide (II) which can be prepared in thismanner are shown in Table 2; these examples are, however, to beconstrued as merely illustrative, and not limitations of the presentinvention in any way whatsoever.

                  TABLE 2                                                         ______________________________________                                         ##STR6##                                                                     Compound No.         R                                                        ______________________________________                                        (101)                2-OCF.sub.3                                              (102)                3-OCF.sub.3                                              (103)                4-OCF.sub.3                                              (104)                2-OCF.sub.2 H                                            (105)                3-OCF.sub.2 H                                            (106)                4-OCF.sub.2 H                                            (107)                2-OCF.sub.2 CF.sub.2 H                                   (108)                3-OCF.sub.2 CF.sub.2 H                                   (109)                4-OCF.sub.2 CF.sub.2 H                                   (110)                4-OCF.sub.2 Cl                                           ______________________________________                                    

When used as an active ingredient of microbicidal compositions, theisothiazolone derivative (I) of the present invention can be in anypossible form. The isothiazolone derivative (I) may be used as such ordiluted with water, an organic solvent, a powdery substance or otherappropriate carriers. Alternatively, the isothiazolone derivative (I)may be mixed with an appropriate liquid or solid carrier and preparedinto various formulations such as wettable powders, liquid formulations,emulsifiable concentrates, dusts, granules or fine granules by aconventional method for preparation of microbicides. If necessary,wetting agents, dispersing agents, emulsifiers, lubricants and otherauxiliary agents may be added to these formulations.

Each formulation contains the isothiazolone derivative (I) as an activeingredient in an amount of 1% to 99% by weight, preferably 10% to 90% byweight, based on the total weight of the formulation.

The liquid carrier used for formulation should serve as a solvent of theisothiazolone derivative (I) or should be able to disperse or dissolvethe isothiazolone derivative (I) with the aid of auxiliary agents.Examples of the liquid carrier are water, methanol and dimethylsulfoxide. Examples of the solid carrier are silica gel, diatomaceousearth, alumina, talc, calcium carbonate and clay. Typical examples ofthe auxiliary agent are acetone and hexane.

When used as an active ingredient of microbicidal compositions, theisothiazolone derivative (I) can be contained at an appropriateconcentration which is determined depending upon the properties oftarget microorganisms. The optimum concentration can be determined bysystematic examinations. In general, the desirable concentration of theisothiazolone derivative (I) is 0.01 to 100,000 ppm, based on the weightof a material to be protected.

The microbicidal composition containing the isothiazolone derivative (I)of the present invention as an active ingredient is useful forpreventing or inhibiting the growth of microorganisms in industrialfields, especially.

The present invention will be further illustrated by the followingProduction Examples, Reference Example and Test Example, which are to beconstrued as merely illustrative, and not limitations of the presentinvention in any way whatsoever. The respective compounds are designatedby the corresponding numbers shown in Tables 1 and 2.

Production Example 1

Preparation of compounds (3) and (23)

First, 18.73 g ofN,N'-di(4-trifluoromethoxyphenyl)-3,3'-dithiopropionamide was suspendedin 200 ml of toluene, after which 23.92 g of sulfuryl chloride was thenadded dropwise to the suspension at room temperature, and the resultantmixture was stirred for 12 hours. After completion of the reaction, thereaction mixture was concentrated, and 250 ml of a saturated aqueoussolution of sodium hydrogencarbonate was added to the concentrate withtaking care to prevent foaming. The product was extracted with ethylacetate. The organic layer was washed with water, dried with magnesiumsulfate, and concentrated. The concentrate was purified by columnchromatography (hexane: ethyl acetate=3:1 to 1:1) to give 6.4 g of2-(4-trifluoromethoxyphenyl)-4-isothiazolin-3-on (compound (3); m.p.,117°-118° C.) and 5.1 g of 2-(4-trifluoromethoxyphenyl)-5-chloro-4-isothiazolin-3-on (compound (23); m.p., 51°-52° C.)

Production Example 2

Preparation of compound (13)

First, a mixture containing 6.4 g of2-(4-trifluorornethoxyphenyl)-4-isothiazolin-3-on and 5.1 g of2-(4-trifluoromethoxyphenyl)-5-chloro-4-isothiazolin-3-on was suspendedin 100 ml of dichloromethane, after which 19 g of sulfuryl chloride wasthen added dropwise to the suspension dropwise at room temperature, andthe resultant mixture was stirred for 12 hours. After completion of thereaction, 200 ml of a saturated aqueous solution of sodiumhydrogencarbonate was added to the reaction mixture, and thedichloromethane layer was separated. The aqueous layer was extractedwith 150 ml of dichloromethane. The combined dichloromethane layer waswashed with water, dried with magnesium sulfate, and concentrated. Theconcentrate was purified by column chromatography (hexane: ethylacetate=6:1) to give 4 g of2-(4-trifluoromethoxyphenyl)-4,5-dichloro-4-isothiazolin-3-on (compound(13); m.p., 129°-130° C.).

Production Example 3

Preparation of compound (103)

First, a mixture containing 100 g of p-trifluoromethoxyaniline, 700 mlof toluene and 98.2 g of pyridine was cooled to 0° C., after which 69.7g of 3,3'-dithiopropionic acid dichloride were added dropwise to themixture, and the resultant mixture was stirred at room temperature(approximately 20° C.) for 1 hour and then at 80° C. for 2 hours. Aftercompletion of the reaction, the solvent was removed from the reactionmixture, and 500 ml of a 5% aqueous solution of hydrochloric acid wasadded to the residue for crystallization, and the deposited crystalswere collected by filtration. The crystals were washed with water anddried under reduced pressure to give 160.3 g ofN,N'-di(4-trifluoromethoxyphenyl)-3,3'-dithiopropionamide.

¹ H-NMR (CDCI₃ -DMSO-d⁶) δ (ppm): 10.3 (brs, 2H), 7.7 (d, 4H), 7.1 (d,4H), 2.9 (m, 8H)

IR (KBr): 3310 cm⁻¹, 1661 cm⁻¹

Reference Example 1

Preparation of 3,3'-dithiopropionic acid dichloride

First, 100 g of 3,3'-dithiopropionic acid was added to 500 ml oftoluene, after which 2.5 ml of N,N-dimethylformamide was added to themixture and 135.5 g of thionyl chloride was then added dropwise to themixture, the resultant mixture was stirred at 50° C. for 2 hours. Aftercompletion of the reaction, the toluene was removed from the reactionmixture, which gave 122 g of 3,3'-dithiopropionic acid dichloride as abrown liquid.

¹ H-NMR (CDCI₃) δ (ppm): 3.3 (4H, t), 3.0 (4H, t)

IR (neat): 1800 cm⁻¹

Test Example 1

Each test compound was dissolved in dimethyl sulfoxide, and the solutionwas mixed with potato dextrose agar (PDA) so as to have a predeterminedconcentration. Various fungi were independently inoculated on thecompound-containing PDAs and cultured at 27° C. for 5 days, after whichthe growth of the fungi was evaluated. The results are shown in Table 3,as the minimum inhibitory concentration (M.I.C.) in ppm against eachspecies of the fungi tested.

                  TABLE 3                                                         ______________________________________                                                Fungi tested*                                                         Compound No.                                                                            Aa      An    Ap     Cc  Pf    Cg  Fo                               ______________________________________                                         (3)      4       4     4      4   4     4   20                               (13)      4       4     4      4   4     4    4                               ______________________________________                                         *Aa: Alternaria alternata                                                     An: Aspergillus niger                                                         Ap: Aureobasidium pullulans                                                   Cc: Cladosporium cladosporioides                                              Pf: Penicillium funiculosum                                                   Cg: Chaetomium globosum                                                       Fo: Fusarium oxysporum                                                   

Test Example 2

Each test compound was dissolved in dimethyl sulfoxide, and the solutionwas mixed with an LB liquid medium so as to have a predeterminedconcentration. Various bacteria were independently inoculated in thecompound-containing liquid media and cultured with shaking at 30° C. for1 day, after which the growth of the bacteria was evaluated. The resultsare shown in Table 4, as the minimum inhibitory concentration (M.I.C.)in ppm against each species of the bacteria tested.

                  TABLE 4                                                         ______________________________________                                                 Bacteria tested*                                                     Compound No.                                                                             Bs      Cb       Fa    Ml     Sa                                   ______________________________________                                         (3)       <0.08   0.4      2.0   2.0    2.0                                  (13)       0.4     <0.08    <0.08 <0.08  <0.08                                ______________________________________                                         *Bs: Bacillus subtilis                                                        Cb: Clostoridium butyrcum                                                     Fa: Flavobacterium aquatile                                                   Ml: Micrococcus luteus                                                        Sa: Staphylococcus aureus                                                

Test Example 3

In sterile distilled water containing the test compound or referencecompound at a predetermined concentration was inoculated bacteria(Pseudomonas fluorescens) at a concentration of 10⁶ cfu/ml, and thebacterial suspension was shaken (170 rpm) at 30° C. After 4 and 8 hoursfrom the treatment, part of the bacterial suspension was taken andinoculated on an LB agar medium with a spiral plater, followed bystationary cultivation at 30° C. for 2 days. The viable cell count(cfu/ml) was measured for the determination of bactericidal rates. Theresults are shown in Table 5. The bactericidal rate (%) was determinedby the following equation. ##EQU1##

                  TABLE 5                                                         ______________________________________                                                Concentration                                                                           Bactericidal rates                                          Compound No.                                                                            (ppm)       after 4 hours                                                                             after 8 hours                               ______________________________________                                        (13)      1           53          >99                                         Ref Compd.*.sup.)                                                                       1           27          23                                          ______________________________________                                         *.sup.) The reference compound is of the formula:                             ##STR7##                                                                 

As described above, the isothiazolone derivative (I) of the presentinvention has excellent effects of destroying or inhibitingmicroorganisms such as bacteria and fungi. In particular, such effectsare satisfactory at the initial stage and sustainable for a long periodof time. Thus, the isothiazolone derivative (I) of the present inventioncan find a wide variety of applications as a microbicide.

What is claimed is:
 1. An isothiazolone derivative of the formula:##STR8## wherein X¹ and X² are the same or different and areindependently hydrogen, chlorine or bromine; and R is haloalkoxy.
 2. Anisothiazolone derivative according to claim 1, wherein R isfluoroalkoxy.
 3. An isothiazolone derivative according to claim 1,wherein R is trifluoromethoxy.
 4. An isothiazolone derivative accordingto any one of claims 1 to 3, wherein X¹ and X² are both hydrogen orchlorine.
 5. A microbicidal composition comprising as an activeingredient a microbicidally effective mount of the isothiazolonederivative according to claim 1, and an inert carrier or diluent.
 6. Amethod for destroying or inhibiting microorganisms, which comprisesapplying a microbicidally effective amount of the isothiazolonederivative according to claim 1 to microorganisms.